It is known in the pharmaceutical art to prepare compositions which provide for controlled release of pharmacologically active substances contained in the compositions after oral administration to humans and animals. Such slow release compositions can be used to delay absorption of a medicament until it has reached certain portions of the alimentary tract. Such sustained-release of a medicament in the alimentary tract further maintains a desired concentration of said medicament in the blood stream for a longer duration than would occur if conventional rapid release dosage forms are administered. Such controlled release dosage forms are believed to lead to improvement in patient therapy.
For example, typical dosing regimens for a class of antibiotics called macrolide antibiotics are two, three or four times per day. These dosing regimens have proved disadvantageous for macrolide antibiotics, as well as other medicaments, because of lack of convenience, and more importantly, lack of compliance. Thus, many techniques have been used to provide controlled and extended-release pharmaceutical dosage forms in order to maintain therapeutic serum levels of medicaments and to minimize the effects of missed doses of drugs cause by a lack of patient compliance.
It is typically the goal of all sustained-release preparations to provide a longer period of pharmacologic response after the administration of the dosage form than that which is ordinarily experienced after the administration of the rapid release dosage forms. However, it is often not possible to readily predict whether a particular sustained release formulation will provide the desired sustained release for a relatively sparingly soluble to insoluble drug, and it has generally been found that it is necessary to carry out considerable experimentation to obtain sustained release formulations of such drugs having the desired bioavailability when ingested.
Generally, it is known that the absorption and bioavailability of any particular therapeutic agent, including sustained release formulations containing therapeutic agents can be affected by numerous factors when dosed orally. Such factors typically include, but are not limited to, the presence of food in the gastrointestinal (GI) tract. The presence of food in the GI tract usually causes the gastric residence time of a drug to be significantly longer than if administered in the fasted state. If the bioavailability of a drug is affected beyond a certain point due to the presence of food in the GI tract, the drug is said to exhibit a “food effect”.
When a drug exhibits an adverse food effect, there is possible risk associated with administering it to a patient who has eaten recently, including but not limited to, the potential that absorption into the bloodstream may be adversely affected to the point that the patient risks insufficient absorption to treat the condition for which the drug was administered. Additionally, drugs which are decomposition-sensitive to pH can be affected as the pH of the stomach varies, between the fed and fasted state, with the amount of food therein. Numerous other factors can also be involved in the absorption and bioavailability of a particular drug, and there usually is no way to predict, in the absence of actual testing, whether a particular drug will exhibit a “food effect”. Toothaker and Welling, Ann. Rev. Pharmacol. Toxicol., 1980, 173-99, discuss various drugs whose absorption is delayed in the presence of food (cephalexin, cefaclor, metronidazole, aspirin, alclofenac, indoprofen, digoxin, cimetidine), whose absorption may be unaffected by food (ampicillin, erythromycin estolate, spiramycin, propylthiouracil, oxazepam, bendroflumethiazide), and whose absorption is increased in the presence of food (erythromycin ethylsuccinate, nitrofurantoin, 8-methoxsalen, propranolol, metoprolol, dicoumarol, diazepam, hydrochlorothiazide).
Generally it is known in the art that certain sustained release formulations exhibit a “food effect.” Often to avoid such food effect, enteric coatings may be used, allowing the drug to pass through the full (fed) stomach and be absorbed in the intestine. These formulations do not release significant amounts of active ingredient until the dosage form is in the higher pH environment of the small intestine. However, certain active ingredients may have decreased solubility in higher pH's, and are therefore not absorbed well in the intestine.
In view of the aforementioned, there exists a need in the art to provide a controlled release formulation for sparingly soluble to insoluble drugs. In addition, a further need exists to provide a controlled release formulation for sparingly soluble to insoluble drugs which does not exhibit a significant food effect. Accordingly, the present invention provides a novel controlled release formulation comprising a drug which has a solubility of less than about 1 part drug in 30 parts water, which provides for a gradual release of the drug without a substantial or significant fed effect and methods for preparation of the same.